These parameters were developed by the Joint Task Force on Practice Parameters (JTFPP), representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, ...Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma & Immunology. The AAAAI and ACAAI have jointly accepted responsibility for establishing “The diagnosis and management of acute and chronic urticaria: 2014 update.” This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the JTFPP, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. The JTFPP understands that the cost of diagnostic tests and therapeutic agents is an important concern that might appropriately influence the work-up and treatment chosen for a given patient. The JTFPP recognizes that the emphasis of our primary recommendations regarding a medication might vary, for example, depending on third-party payer issues and product patent expiration dates. However, because a given test or agent's cost is so widely variable and there is a paucity of pharmacoeconomic data, the JTFPP generally does not consider cost when formulating practice parameter recommendations. In extraordinary circumstances, when the cost/benefit ratio of an intervention is prohibitive, as supported by pharmacoeconomic data, commentary might be provided. These parameters are not designed for use by pharmaceutical companies in drug promotion. The JTFPP is committed to ensuring that the practice parameters are based on the best scientific evidence that is free of commercial bias. To this end, the parameter development process includes multiple layers of rigorous review. These layers include the workgroup convened to draft the parameter, the task force reviewers, and peer review by members of each sponsoring society. Although the task force has the final responsibility for the content of the documents submitted for publication, each reviewer comment will be discussed, and reviewers will receive written responses to comments, when appropriate. To preserve the greatest transparency regarding potential conflicts of interest, all members of the JTFPP and the practice parameter workgroups will complete a standard potential conflict of interest disclosure form, which will be available for external review by the sponsoring organization and any other interested individual. In addition, before confirming the selection of a Work Group chairperson, the Joint Task Force will discuss and resolve all relevant potential conflicts of interest associated with this selection. Finally, all members of parameter workgroups will be provided a written statement regarding the importance of ensuring that the parameter development process is free of commercial bias. Practice parameters are available online at www.jcaai.org and www.allergyparameters.org.
Clinical exome sequencing is nondiagnostic for about 75% of patients evaluated for a possible Mendelian disorder. We examined the ability of systematic reevaluation of exome data to establish ...additional diagnoses.
The exome and phenotypic data of 40 individuals with previously nondiagnostic clinical exomes were reanalyzed with current software and literature.
A definitive diagnosis was identified for 4 of 40 participants (10%). In these cases the causative variant is de novo and in a relevant autosomal-dominant disease gene. The literature to tie the causative genes to the participants’ phenotypes was weak, nonexistent, or not readily located at the time of the initial clinical exome reports. At the time of diagnosis by reanalysis, the supporting literature was 1 to 3 years old.
Approximately 250 gene–disease and 9,200 variant–disease associations are reported annually. This increase in information necessitates regular reevaluation of nondiagnostic exomes. To be practical, systematic reanalysis requires further automation and more up-to-date variant databases. To maximize the diagnostic yield of exome sequencing, providers should periodically request reanalysis of nondiagnostic exomes. Accordingly, policies regarding reanalysis should be weighed in combination with factors such as cost and turnaround time when selecting a clinical exome laboratory.
Pseudouridine is the most abundant RNA modification, yet except for a few well-studied cases, little is known about the modified positions and their function(s). Here, we develop Ψ-seq for ...transcriptome-wide quantitative mapping of pseudouridine. We validate Ψ-seq with spike-ins and de novo identification of previously reported positions and discover hundreds of unique sites in human and yeast mRNAs and snoRNAs. Perturbing pseudouridine synthases (PUS) uncovers which pseudouridine synthase modifies each site and their target sequence features. mRNA pseudouridinylation depends on both site-specific and snoRNA-guided pseudouridine synthases. Upon heat shock in yeast, Pus7p-mediated pseudouridylation is induced at >200 sites, and PUS7 deletion decreases the levels of otherwise pseudouridylated mRNA, suggesting a role in enhancing transcript stability. rRNA pseudouridine stoichiometries are conserved but reduced in cells from dyskeratosis congenita patients, where the PUS DKC1 is mutated. Our work identifies an enhanced, transcriptome-wide scope for pseudouridine and methods to dissect its underlying mechanisms and function.
Display omitted
•Ψ-seq for high resolution, transcriptome-wide profiling of pseudouridine•Many distinct sites in mRNA; dynamically regulated in heat shock•Sites depend on conserved cognate pseudouridine synthases in yeast and human•Reduced rRNA and TERC pseudouridine in dyskeratosis congenita patients
Transcriptome-wide pseudouridine mapping reveals extensive, dynamic pseudouridylation of mRNA and noncoding RNA in yeast and human.
RAD51 Gene Family Structure and Function Bonilla, Braulio; Hengel, Sarah R; Grundy, McKenzie K ...
Annual review of genetics,
11/2020, Letnik:
54, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Accurate DNA repair and replication are critical for genomic stability and cancer prevention.
RAD51
and its gene family are key regulators of DNA fidelity through diverse roles in double-strand break ...repair, replication stress, and meiosis. RAD51 is an ATPase that forms a nucleoprotein filament on single-stranded DNA. RAD51 has the function of finding and invading homologous DNA sequences to enable accurate and timely DNA repair. Its paralogs, which arose from ancient gene duplications of
RAD51
, have evolved to regulate and promote RAD51 function. Underscoring its importance, misregulation of RAD51, and its paralogs, is associated with diseases such as cancer and Fanconi anemia. In this review, we focus on the mammalian RAD51 structure and function and highlight the use of model systems to enable mechanistic understanding of RAD51 cellular roles. We also discuss how misregulation of the
RAD51
gene family members contributes to disease and consider new approaches to pharmacologically inhibit RAD51.
Variant pathogenicity classifiers such as SIFT, PolyPhen-2, CADD, and MetaLR assist in interpretation of the hundreds of rare, missense variants in the typical patient genome by deprioritizing some ...variants as likely benign. These widely used methods misclassify 26 to 38% of known pathogenic mutations, which could lead to missed diagnoses if the classifiers are trusted as definitive in a clinical setting. We developed M-CAP, a clinical pathogenicity classifier that outperforms existing methods at all thresholds and correctly dismisses 60% of rare, missense variants of uncertain significance in a typical genome at 95% sensitivity.
Buildings consume nearly 40% of primary energy production globally. Certified green buildings substantially reduce energy consumption on a per square foot basis and they also focus on indoor ...environmental quality. However, the co-benefits to health through reductions in energy and concomitant reductions in air pollution have not been examined.We calculated year by year LEED (Leadership in Energy and Environmental Design) certification rates in six countries (the United States, China, India, Brazil, Germany, and Turkey) and then used data from the Green Building Information Gateway (GBIG) to estimate energy savings in each country each year. Of the green building rating schemes, LEED accounts for 32% of green-certified floor space and publically reports energy efficiency data. We employed Harvard's Co-BE Calculator to determine pollutant emissions reductions by country accounting for transient energy mixes and baseline energy use intensities. Co-BE applies the social cost of carbon and the social cost of atmospheric release to translate these reductions into health benefits. Based on modeled energy use, LEED-certified buildings saved $7.5B in energy costs and averted 33MT of CO
, 51 kt of SO
, 38 kt of NO
, and 10 kt of PM
from entering the atmosphere, which amounts to $5.8B (lower limit = $2.3B, upper limit = $9.1B) in climate and health co-benefits from 2000 to 2016 in the six countries investigated. The U.S. health benefits derive from avoiding an estimated 172-405 premature deaths, 171 hospital admissions, 11,000 asthma exacerbations, 54,000 respiratory symptoms, 21,000 lost days of work, and 16,000 lost days of school. Because the climate and health benefits are nearly equivalent to the energy savings for green buildings in the United States, and up to 10 times higher in developing countries, they provide an important and previously unquantified societal value. Future analyses should consider these co-benefits when weighing policy decisions around energy-efficient buildings.
The RecQ DNA helicases in DNA repair Bernstein, Kara A; Gangloff, Serge; Rothstein, Rodney
Annual review of genetics,
01/2010, Letnik:
44
Journal Article
Recenzirano
Odprti dostop
The RecQ helicases are conserved from bacteria to humans and play a critical role in genome stability. In humans, loss of RecQ gene function is associated with cancer predisposition and/or premature ...aging. Recent experiments have shown that the RecQ helicases function during distinct steps during DNA repair; DNA end resection, displacement-loop (D-loop) processing, branch migration, and resolution of double Holliday junctions (dHJs). RecQ function in these different processing steps has important implications for its role in repair of double-strand breaks (DSBs) that occur during DNA replication and meiosis, as well as at specific genomic loci such as telomeres.
Angioedema is defined as localized and self‐limiting edema of the subcutaneous and submucosal tissue, due to a temporary increase in vascular permeability caused by the release of vasoactive ...mediator(s). When angioedema recurs without significant wheals, the patient should be diagnosed to have angioedema as a distinct disease. In the absence of accepted classification, different types of angioedema are not uniquely identified. For this reason, the European Academy of Allergy and Clinical Immunology gave its patronage to a consensus conference aimed at classifying angioedema. Four types of acquired and three types of hereditary angioedema were identified as separate forms from the analysis of the literature and were presented in detail at the meeting. Here, we summarize the analysis of the data and the resulting classification of angioedema.
Background There is growing public awareness regarding the risk associated with poor indoor air quality in the home and workplace. Because Americans spend approximately 22 hours every day indoors, ...susceptible individuals are at much greater risk of adverse health effects from chronic low levels of exposure to indoor air pollutants over time. Along with particulate matter, gases such as ozone, nitrogen dioxide, carbon monoxide, and sulfur dioxide; microbial and chemical volatile organic compounds; passive smoke; and outdoor ambient air are the most common types of air pollutants encountered indoors. Objective To provide the allergists with necessary information that will assist them in making useful recommendations to patients seeking advice regarding indoor environmental triggers beyond traditional perennial allergens. Methods Review of the literature pertaining to indoor exposure and health effects of gaseous and particular matter. Results Indoor pollutants act as respiratory irritants, toxicants, and adjuvants or carriers of allergens. Conclusion The allergist should be prepared to evaluate patient exposure to allergic and nonallergic triggers and understand how outdoor air pollution is affecting indoor environments. This requires being familiar with methodologies for monitoring and interpreting indoor air quality and interpreting results in the context of the patients exposure history and advising patients about rational environmental control interventions.
The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and ...their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the Ca
1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.
PDF
